* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With triethylamine In dichloromethane at 20℃; for 2.16667 h; Cooling with ice
Amine (132 g, 401 mmol) was suspended in dichloromethane (1000 ml) under ice-cooling. Triethylamine (123 ml, 882 mmol) and (Boc)2O (101 ml, 440 mmol) were sequentially added thereto and stirred for 10 minutes. After that, the mixture was stirred at room temperature for 2 hours and the solvent was removed. The residue was poured into aqueous citric acid (citric acid monohydrate 50 g in water 400 ml) to become pH4 and extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate anhydrous. The solvent was removed under reduced pressure to quantitatively give the target compound.1H-NMR (DMSO-d6) δ ppm: 1.06-1.25 (m, 2H), 1.25-1.43 (m, 2H), 1.37 (s, 9H), 1.75-1.94 (m, 4H), 2.19 (tt, 1H, J=11.7, 3.9 Hz), 3.07-3.24 (m, 1H), 3.58 (s, 3H), 6.74 (d, 1H, J=6.6 Hz).
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1 h;
Step 1 trans-Methyl 4-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate To a suspension of trans-methyl 4-aminocyclohexanecarboxylate hydrochloride (1.5 g, 7.7 mmol) in DCM (80 mL) was added DIEA (4 g, 31mmol) and (Boc)20 (3 g, 13.9 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuum to give crude product. The crude product was purified by silica gel chromatography (PE / EtOAc = 8 : 1 to 3 : 1) to give trans-methyl 4-((iert-butoxycarbonyl)amino)cyclohexanecarboxylate (1.7 g, yield 86percent) as a white solid. 1H NMR (400 MHz, Methanol-d4) δ 4.38 (br, 1H), 3.66 (s, 3H), 3.47- 3.40 (m, 1H), 2.22-2.19 (m, 1H), 2.07-1.98 (m, 4H), 1.56-1.50 (m, 2H), 1.43 (s, 9H), 1.15-1.12 (m, 2H).
In nitrogen atmosphere, to a solution of trans- 1,4-cyclohexane-dicarboxylic acid monomethyl ester (A3-1) (lOOg, 0.538mol, l .Oeq) and triethylamine (57.4g, 0.568mol, 1.055eq) in t-butyl alcohol (lOOOmL) was added dropwise diphenylphosphoryl azide (155g, 0.563mol, 1.047eq) at room temperature. The mixture was refluxed over 16hrs. Upon completion by TLC, the mixture was then cooled and concentrated. Water (lOOOmL) was added, and the mixture was extracted three times with MTBE. Then the organic layer was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give compound A3 -2 as an off-white powder (53g, yield 39.2percent). MS-ESI:[M+1]+: 257.1
To (frans)-4-(methoxycarbonyl)cyclohexanecarboxylic acid (2.5 mg, 13 mmol) in tert- butanol (25 mL) was added diphenyl phosphorazidate (3.88 g, 14 mmol) and triethylamine (1 .97 mL, 14 mmol). The mixture was heated at 60 °C for 1 h and then at reflux overnight. After cooling to room temperature, the mixture was quenched into ice water and extracted with EtOAc. The combined organics were washed with sat. NaHC03 and brine, dried over Na2S04, filtered, and concentrated. The residue was dissolved in MeOH (6 mL) and to this was added water (18 mL). After stirring for ca. 1 h on ice, the resulting solid was collected by filtration, and washed with 3:1 water:MeOH, and hexanes to give the title compound as a white solid (2.32 g, 67percent yield). 1H NMR (400 MHz, CD3SOCD3) δ 1 .05-1 .20 (m, 2 H), 1 .25-1 .44 (m, 1 1 H), 1 .72- 1 .91 (m, 4 H), 2.17 (tt, J = 12, 3 Hz, 1 H), 3.06-3.21 (m, 1 H), 3.56 (s, 3 H), 6.72 (d, J = 8 Hz, 1 H).
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃;
A suspension of LiAlH4(9.0g, 0.236mol, 1.12eq) in THF (500mL) was cooled to 0°C in ice-bath, and then added a solution of compound A3-2 (54.3g, 0.21 lmol, l .Oeq) in THF (200mL) while keeping the temperature below 10°C. The reaction mixture was stirred overnight at room temperature, and then quenched with sodium sulfate decahydrate (27g) at 15°C to 25°C, filtered and the filtrate was concentrated to give compound A3-3 as a white powder (43g, yield 89percent). MS-ESI:[M+1]+: 229.1
89%
With sodium tetrahydroborate; calcium chloride In tetrahydrofuran; ethanol at 20℃;
To a solution of (frans)-methyl 4-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate (Intermediate 18A) (1 .5 g, 5.8 mmol) in EtOH (24 mL) and THF (2.7 mL), cooled on ice, was added calcium chloride (1 .29 g, 1 1 .7 mmol) portion wise to give a milky suspension. NaBH4 (882 mg, 23.3 mmol) was then added portion wise over ca. 25 min and the reaction was stirred on ice for 1 h. The bath was removed and the mixture was allowed to stir at room temperature overnight. The reaction was cooled to 10 °C and to this was added 5percent aqueous K2CO3 (5.4 mL) dropwise, to give a pH of ca. 1 1 . A white precipitate formed and was isolated by filtration. The solid was stirred with EtOAc (50 mL) and water (14 mL). The layers were separated and the organic layer was washed with 0.5 M aqueous HCI (5 mL), water and brine, dried over MgS04, filtered, and concentrated to give the title compound (474 mg) as a white solid. The initial filtrate was concentrated, then dilute with saturated aqueous NH4CI and extracted with EtOAc (3X). Combined organics were washed with brine and dried over Na2SC>4, filtered, and concentrated to give the title compound (724 mg) as a white solid. Total isolated product was 1 .1 9 g (89percent yield). 1H NMR (400 MHz, CD3SOCD3) δ 0.78-0.93 (m, 2 H), 1 .01 -1 .15 (m, 2 H), 1 .35 (s, 9 H), 1 .64-1 .80 (m, 4 H), 3.10 (d, J = 8 Hz, 1 H), 3.16 (t, J = 6 Hz, 2 H), 4.33 (t, J = 5 Hz, 1 H), 6.64 (d, J = 8 Hz, 1 H).
With diphenyl phosphoryl azide; triethylamine; at 100℃; for 16h;Inert atmosphere;
In nitrogen atmosphere, to a solution of trans- 1,4-cyclohexane-dicarboxylic acid monomethyl ester (A3-1) (lOOg, 0.538mol, l .Oeq) and triethylamine (57.4g, 0.568mol, 1.055eq) in t-butyl alcohol (lOOOmL) was added dropwise diphenylphosphoryl azide (155g, 0.563mol, 1.047eq) at room temperature. The mixture was refluxed over 16hrs. Upon completion by TLC, the mixture was then cooled and concentrated. Water (lOOOmL) was added, and the mixture was extracted three times with MTBE. Then the organic layer was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give compound A3 -2 as an off-white powder (53g, yield 39.2%). MS-ESI:[M+1]+: 257.1
With diphenyl phosphoryl azide; triethylamine; In tert-butyl alcohol; at 60℃; for 18h;Heating / reflux;
(3) Trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (100.0 g) obtained in (2) above is dissolved in t-butanol (1000 ml), and thereto are added diphenylphosphoryl azide (155 g) and triethylamine (78.6 ml). The mixture is heated at about 60C for an hour and further heated under reflux for additional 17 hours. After allowing to cool, to the reaction solution is added ice-water, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is dissolved in methanol (250 ml), and thereto is added water (750 ml) and the mixture is stirred under ice-cooling. After 0.5 hours, the precipitates are collected by filtration, washed with water/methanol (3:1, 1000 ml) and n-hexane successively and dried to give the title compound (117.0 g). APCI-MS M/Z: 275[M+H]+.
With diphenyl phosphoryl azide; triethylamine; at 60℃; for 18h;Heating / reflux;
(1) To a solution of monomethyl trans-cyclohexane-1,4-dicarboxylate (compound obtained in the above Reference Example Al(2), 100.0 g) in tert-buthanol (1000 mL) was added diphenylphosphoryl azide (155 g) and triethylamine (78.6 mL) and the mixture was stirred at 60 C for 1 hour and then refluxed under heating for 17 hours. After cooling, to the reaction mixture was added ice-water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution and brine, dried over sodium sulfate and concentrated in vacuo. To a solution of the resultant residue in methanol (250 mL) was added water (750 mL) and the mixture was stirred under ice-cooling for 30 minutes. The precipitates were collected by filtration, washed successively with water/methanol (3:1, 1000 mL) and n-hexane and dried to give methyl trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylate (117.0 g). MS(APCI)m/z; 275 [M+H]+
With lithium aluminium tetrahydride; In tetrahydrofuran; dichloromethane;
Example 23.2 A solution of 1.52 g (40 mmol) LAH in 7 ml THF was refluxed and treated for 2.5 h with a solution of 5.15 g (20 mmol) of trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid methyl ester in 35 ml THF. The reaction was heated for 15 h, cooled (0 C.) and hydrolyzed with 10 ml water. The mixture was diluted with THF, dried over Na2SO4, filtered and evaporated. The residue was dissolved in CH2Cl2, dried over Na2SO4, filtered and evaporated to yield 2.89 g (100%) of trans-(4-Methylamino-cyclohexyl)-methanol, mp: 87-88 C.; MS: 143 (M).
With triethylamine; In dichloromethane; at 0 - 20℃; for 2.16667h;
Amine (132 g, 401 mmol) was suspended in dichloromethane (1000 ml) under ice-cooling. Triethylamine (123 ml, 882 mmol) and (Boc)2O (101 ml, 440 mmol) were sequentially added thereto and stirred for 10 minutes. After that, the mixture was stirred at room temperature for 2 hours and the solvent was removed. The residue was poured into aqueous citric acid (citric acid monohydrate 50 g in water 400 ml) to become pH4 and extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate anhydrous. The solvent was removed under reduced pressure to quantitatively give the target compound. 1H-NMR (DMSO-d6) deltappm: 1.06-1.25 (m, 2H), 1.25-1.43 (m, 2H), 1.37 (s, 9H), 1.75-1.94 (m, 4H), 2.19 (tt, 1H, J = 11.7, 3.9 Hz), 3.07-3.24 (m, 1H), 3.58 (s, 3H), 6.74 (d, 1H, J = 6.6 Hz).
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃;
A suspension of LiAlH4(9.0g, 0.236mol, 1.12eq) in THF (500mL) was cooled to 0C in ice-bath, and then added a solution of compound A3-2 (54.3g, 0.21 lmol, l .Oeq) in THF (200mL) while keeping the temperature below 10C. The reaction mixture was stirred overnight at room temperature, and then quenched with sodium sulfate decahydrate (27g) at 15C to 25C, filtered and the filtrate was concentrated to give compound A3-3 as a white powder (43g, yield 89%). MS-ESI:[M+1]+: 229.1
89%
With sodium tetrahydroborate; calcium chloride; In tetrahydrofuran; ethanol; at 20℃;
To a solution of (frans)-<strong>[146307-51-9]methyl 4-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate</strong> (Intermediate 18A) (1 .5 g, 5.8 mmol) in EtOH (24 mL) and THF (2.7 mL), cooled on ice, was added calcium chloride (1 .29 g, 1 1 .7 mmol) portion wise to give a milky suspension. NaBH4 (882 mg, 23.3 mmol) was then added portion wise over ca. 25 min and the reaction was stirred on ice for 1 h. The bath was removed and the mixture was allowed to stir at room temperature overnight. The reaction was cooled to 10 C and to this was added 5% aqueous K2CO3 (5.4 mL) dropwise, to give a pH of ca. 1 1 . A white precipitate formed and was isolated by filtration. The solid was stirred with EtOAc (50 mL) and water (14 mL). The layers were separated and the organic layer was washed with 0.5 M aqueous HCI (5 mL), water and brine, dried over MgS04, filtered, and concentrated to give the title compound (474 mg) as a white solid. The initial filtrate was concentrated, then dilute with saturated aqueous NH4CI and extracted with EtOAc (3X). Combined organics were washed with brine and dried over Na2SC>4, filtered, and concentrated to give the title compound (724 mg) as a white solid. Total isolated product was 1 .1 9 g (89% yield). 1H NMR (400 MHz, CD3SOCD3) delta 0.78-0.93 (m, 2 H), 1 .01 -1 .15 (m, 2 H), 1 .35 (s, 9 H), 1 .64-1 .80 (m, 4 H), 3.10 (d, J = 8 Hz, 1 H), 3.16 (t, J = 6 Hz, 2 H), 4.33 (t, J = 5 Hz, 1 H), 6.64 (d, J = 8 Hz, 1 H).
83%
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 23℃; for 2.33333h;Inert atmosphere;
To a 500 mL 3-neck round bottom flask that was flame dried and purged with N2 was addeddry THF (18.0mL). The flask was cooled to 0 C and lithium aluminum hydride (0.720 g, 18.9mmol) was added portion-wise over 5 min. The slurry was stirred at 0 C for 10 minutes, then asolution of methyl 4-(tert-butoxycarbonylamino)cyclohexanecarboxylate (S8, 4.05 g, 15.7mmol) in THF (78.5 mL) was added dropwise over 30 min. The reaction was stirred at 0 C for10 min., then warmed to 23 C and stirred for 2 h. The reaction was cooled to 0 C and ice coldTHF:H2O (1:1, 1.4 mL) was added very slowly. Once bubbling ceased NaOH (2.0 M, 0.7 mL)and H2O (0.7 mL) were added sequentially and the mixture was warmed to 23 C and stirred for3 h. The slurry was filtered and the solids were washed with additional THF (2 × 50 mL). Thefiltrate was concentrated to afford tert-butyl N-[4-(hydroxymethyl)cyclohexyl]carbamate (S9,3.00 g, 83% yield).
31%
With lithium borohydride; In tetrahydrofuran; at 0 - 75℃; for 1h;
To a stirred solution of <strong>[146307-51-9]methyl (1R,4R)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylate</strong> (5.5 g, 21.4 mmol) in THF (20 mL) was added 3 M LiBH4 in THF (16 mL, 43 mmol) dropwise at 0 C. The resulting reaction mixture then heated to 75 C. and stirred for 1 h. The reaction mixture was then transferred into 5% citric acid solution. The pH of the reaction mixture was adjusted to pH 8 to 9 with 8 N NaOH solution. The resulting mixture was then extracted using ethyl acetate (3×100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (25% EAc-Hexanes) to give tert-butyl ((1r,4r)-4-(hydroxymethyl)cyclohexyl)carbamate as white solid (1.5 g, 31%). LC-MS (ESI+) m/z 230.2 (M+H)+.
Lithium aluminum hydride (18.3 g, 483 mmol) was suspended in tetrahydrofuran (800 ml) and ester in tetrahydrofuran (300 ml) obtained in Step 1 was slowly added thereto under ice-cooling with stirring over 1 hour. The mixture was stirred under ice-cooling for 10 minutes and at room temperature for 2.5 hours. The reactant was ice-cooled and the mixture of water and tetrahydrofuran (1:1, 36 ml), 2N aqueous sodium hydroxide (18 ml) and water (18 ml) were sequentially added thereto. The mixture was stirred for 20 minutes and at room temperature for 1.5 hours. The deposit was removed by filtration, the filtrate was condensed under reduced pressure. Ethyl acetate and hexane was added to the residue. The precipitated crystals were collected with filtration to give the desired alcohol (79.5 g, 87 % yield)(through Step 1 to 2). 1H-NMR (DMSO-d6) deltappm: 0.78-1.00 (m, 2H), 1.00-1.32 (m, 3H), 1.37 (s, 9H), 1.65-1.84 (m, 4H), 3.04-3.24 (m, 3H), 4.32-4.42 (m, 1H), 6.66 (d, 1H, J = 7.8 Hz).
Lithium aluminum hydride (18.3 g, 483 mmol) was suspended in tetrahydrofuran (800 ml) and ester in tetrahydrofuran (300 ml) obtained in Step 1 was slowly added thereto under ice-cooling with stirring over 1 hour. The mixture was reacted under ice-cooling for 10 minutes and at room temperature for 2.5 hours. The reactant was ice-cooled and the mixture of water and tetrahydrofuran (1:1, 36 ml), 2 N aqueous sodium hydroxide (18 ml) and water (18 ml) were sequentially added thereto. The mixture was stirred for 20 minutes and at room temperature for 1.5 hours. The deposit was removed by filtration and the filtrate was condensed under reduced pressure. Ethyl acetate and hexane were added to the residue. The precipitated crystals were collected with filtration to give the desired Alcohol (79.5 g, 87% yield) (through Step 1 to 2). 1H-NMR (DMSO-d6) delta ppm: 0.78-1.00 (m, 2H), 1.00-1.32 (m, 3H), 1.37 (s, 9H), 1.65-1.84 (m, 4H), 3.04-3.24 (m, 3H), 4.32-4.42 (m, 1H), 6.66 (d, 1H, J=7.8 Hz).
Step 2: Trans-tert-butyl 4-(hydroxymethyl)cyclohexylcarbamateMethyl trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylate (55.5 g, 216 mmol) was suspended in ethanol (900 ml) and THF (100 ml) and the mixture was cooled to 5C. Granular calcium chloride (47.9g, 431 mmol) was added portionwise to give a milky suspension. Sodium borohydride (32.6 g, 863 mmol) was added portionwise over 25 mins at 5C. The reaction mixture (white emulsion) was stirred at 5C for 1 hour, the water bath was removed and then the reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. The reaction mixture was cooled to 10C and 5% potassium carbonate (200 ml) was added dropwise until the pH of the solution was pH11. A colourless precipitate formed which was filtered off. The solid was stirred with ethyl acetate (2000 ml) and water (500 ml). The organic layer was separated and washed with 0.5M HCI (200 ml), then washed with water (2 x 200 ml) and saturated brine (100 ml). The organic solution was dried over anhydrous MgS04, filtered and evaporated to give a white solid The solid was dried under high vacuum overnight to constant weight; [M+H]+230.
trans-methyl 4-(1-(4-chloro-2-fluorobenzyl)-N-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-6-carboxamido)cyclohexanecarboxylate[ No CAS ]
With diphenyl phosphoryl azide; triethylamine; at 60℃; for 1h;
To (frans)-4-(methoxycarbonyl)cyclohexanecarboxylic acid (2.5 mg, 13 mmol) in tert- butanol (25 mL) was added diphenyl phosphorazidate (3.88 g, 14 mmol) and triethylamine (1 .97 mL, 14 mmol). The mixture was heated at 60 C for 1 h and then at reflux overnight. After cooling to room temperature, the mixture was quenched into ice water and extracted with EtOAc. The combined organics were washed with sat. NaHC03 and brine, dried over Na2S04, filtered, and concentrated. The residue was dissolved in MeOH (6 mL) and to this was added water (18 mL). After stirring for ca. 1 h on ice, the resulting solid was collected by filtration, and washed with 3:1 water:MeOH, and hexanes to give the title compound as a white solid (2.32 g, 67% yield). 1H NMR (400 MHz, CD3SOCD3) delta 1 .05-1 .20 (m, 2 H), 1 .25-1 .44 (m, 1 1 H), 1 .72- 1 .91 (m, 4 H), 2.17 (tt, J = 12, 3 Hz, 1 H), 3.06-3.21 (m, 1 H), 3.56 (s, 3 H), 6.72 (d, J = 8 Hz, 1 H).
A solution of methyl (trans)-4-((tert-butoxycarbonyl)amino)cyclohexane-1- carboxylate (2 g, 7.77 mmol) in toluene (15 mL), under N2, was cooled at -78 C in a dry ice/acetone bath. After stirring for ~10 min, diisobutylaluminum hydride (1.2 M in toluene, 12.95 mL, 15.54 mmol) was added slowly over ~10 min. The mixture was stirred in the cold bath for ~1 h. While in the cold bath, the reaction was quenched by slow, careful addition of a mixture of MeOH (10 mL) and toluene (10 mL). After stirring for ~10 min, the cold bath was removed and aq. satd. potassium sodium tartrate (~50 mL) was added slowly. The mixture was stirred at rt for ~10 min and then it was extracted with Et20 (separation of the phases was problematic because of heavy emulsions). Additional solid potassium sodium tartrate was added, as well as additional water and Et20. Due to heavy emulsions, the biphasic mixture was allowed to stand overnight, which resulted in a clear phase separation. The aqueous phase was extracted 2X with Et20. The Et20 phases were combined, washed with brine, dried over Na2S04, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with 0-40% EtOAc:hexanes gradient to give tert-butyl ((trans)-4-formylcyclohexyl)carbamate (1.64 g, 6.85 mmol, 88% yield) as a white solid. 1H NMR (400 MHz, CD3SOCD3) d ppm 9.55 (s, 1 H), 6.79 (d, J = 8 Hz, 1 H), 3.05-3.24 (m, 1 H), 2.08-2.26 (m, 1 H), 1 .72-1.96 (m, 4 H), 1 .38 (s, 9 H), 1 .08-1.29 (m, 4H).
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